Selected 2-formyl-and 2alpha-(cyanoamidino)-a-nor-5alpha-androstane derivatives



United States Patent 3,424,751 SELECTED Z-FORMYL- AND 2u-(CYANOAMIDINO)-A-NOR-Sa-ANDROSTANE DERIVATIVES Richard M. Scribner, Wilmington, DeL,assignor to E. I.

du Pont de Nemours and Company, Wilmington, Del.,

a corporation of Delaware No Drawing. Filed Oct. 20, 1965, Ser. No.499,017

US. Cl. 260-247.2 10 Claims Int. Cl. C07c 173/10, 171/06 ABSTRACT OF THEDISCLOSURE Described and claimed are: (1) The2-formyl-A-nor-5(at-androstane derivatives of the formula where X is :0or the group where R is hydrogen or a hydrocarbon acyl group of 1 to 12carbons and R is H, CH C H CH CH or CECH, and a is a single bond or adouble bond;

(2) The acetals of these 2-formyl steroids with ethylene or 1,2-propylene glycol; and

(3) The 21x-(cyanoamidino)-A-nor-5a-androstane derivatives of theformula where R and R are as above and Q is alkylene of 4-5 chain carbonatoms and a total of 4-6 carbon atoms or 3-oxa-1, 5-pentylene.

FIELD OF THE INVENTION This invention relates to certain novel steroidcompounds and to processes for preparing them. More specifically, thisinvention is concerned with certain A-nor- Sat-androstane derivativessubstituted in the 2 position with a formyl or a cyanoamidino group.

3,424,751 Patented Jan. 28, 1969 ice DETAILS OF THE INVENTION The novelproducts of the invention are: (1) The 2-forrnyl-A-nor-5a-androstanederivatives of the formula where R is hydrogen or a hydrocarbon acylgroup of 1 to 12 carbons and R is H, CH CH 'CH=CH- or CECH, and a is asingle bond or a double bond;

(2) The acetals of these 2-formyl steroids with lower ethylene or 1,Z-propylene glycol; and

(3) The 2a-(cyanoamidino)-A-nor-Aa-androstane derivatives of the formulawhere R and R are as above and Q is alkylene of 4-5 chain carbon atomsand a total of 4-6 carbon atoms, or is 3-oxa-1,5-pentylene.

The novel 2a-(cyanoamidino)-A-nor-5a-androstanes are prepared byreacting cyanogen azide with a steroid enamine of the formula A Q Nwhere R R and Q are as above, in the temperature range of 0 to 50 C. Theenamine reactant can be prepared by known methods, e.g., by treating a3-ketoandrostane with a secondary cyclic amine of the formula where Q isdefined above, such as pyrrolidine, piperidine, 4meth-ylpiperidine ormorpholine. The enamine is dissolved in a dry inert organic solvent, forexample lower alkyl alkanoates such as methyl acetate, ethyl acetate,ethyl propionate, ethyl butyrate; lower alkanenitriles such asacetonitrile, propionitrile; aromatic hydrocarbons such as benzene,toluene, and the like. A solution of cyanogen azide in a suitablesolvent such as ethyl acetate or acetonitrile is added while maintainingthe temperature in the range of 50C., preferably 15-30C. The reactionmixture is stirred until nitrogen evolution ceases. Pressure is notcritical and atmospheric pressures are employed for convenience.Reaction proportions are not critical, but for preferred results a 1:1ratio of azide to steroid is normally employed. The product is isolatedby filtration orif it is soluble in the solvent, by evaporation of thesolvent. It is either used directly in subsequent reactions, or,preferably, purified by dractionl crystalization or chromatography.

The azide employed must be used in solution, for when it is dry ornearly dry, it is an explosive material.

The novel compounds of Formula I where at is a single bond and X is Rbeing H, CH C l-I or CH=CH i.e., all of the R groups defined aboveexcept CECH, are prepared by reacting a Za-(cyanoamidino) Anor-Sot-andmstane obtained above and having the group with an alkalimetal at a temperature between about -80 and +20 C. in an anhydrous,liquid reaction medium which is a 1-2 carbon monoalkylamine or ammonia,and hydrolyzing the reaction product under neutral to basic conditions.

The 2w(cyanoamidino)-A-nor-5a-androstane is dissolved or dispersed inanhydrous liquid ammonia, methylamine or ethylamine. To this solution orsuspension, which preferably but not necessarily also contains 2-3 molarequivalents of a buffer such as ammonium acetate, is added a slightexcess of an alkali metal (sodium or potassium can be used, but lithiumis preferred) at a temperature between --80 to 20 C. After cessation ofthe initial reaction, as evidenced by abrupt color change from colorlessor yellow to blue, the mixture is stirred for a few minutes and thentreated with excess ammonium chloride until the blue color isdischarged. Addition of water or aqueous base and extraction with anorganic solvent, followed by hydrolysis, conveniently accomplished bychromatography on hydrated alumina, gives the 2-formyl-A-nor-5a-androstane.

The products resulting from the foregoing novel processes can besubjected to further transformation to obtain additional products of theinvention. Thus, the 2-forrnyl- A-nor-5a-androstanes obtained asdescribed in the preceding paragraph can be selectively dehydrogenatedto the corresponding 2-formyl-A-nor-5a-l-androstenes by treatment in thepresence of an acidic catalyst with 2,3-dichloro-S,6-dicyano-p-benzoquinone. The 2-formyl group can beacetalized by treatment with a 1,2-alkanediol such as ethylene glycol or1,2-propylene glycol. From these acetals which also have a 17-ketogroup, the 17a-ethynyl- 2-formyl-A-nor-5wandrostanes or l-androstenesare obtained by reaction with an ethynylating agent such as sodiumacetylide or ethynylmagnesium bromide, followed by hydrolysis of the2-aceta1 group.

Those 2-formyl-A-nor-5a-androstanes or l-androstenes which also have al7fl-hydroxyl can be esterified to obtain the corresponding 17B-acylcompounds. In addition, those 17fi-hydroxyl compounds which have no17a-substituent can be converted to the corresponding 17-keto steroidsby treatment with an appropriate oxidizing agent such as chromiumfrioxide.

The foregoing p s a d pro esses are illustrated in the examples whichfollow.

In these examples, the Greek letter .5 (xi) used in some of the namesand the bond symbol used in some of the formulas signify that the crudeproduce is a mixture of alpha and beta epimers or that the compound isof uncertain configuration.

SPECIFIC EMBODIMENTS OF THE INVENTION Example1.2a-(pyrrolidinocyanoiminomethyl) -A-nor- OH OH s t J '5 L N I NEON"CiJ (N3 it E 3-pyrro1idino-5a-androst-2-en-17 8-01 was prepared byrefluxing a solution of 10 g. (34.5 mmoles) of androstanolone, 10 ml. ofpyrrolidine, and ml. of benzene and collecting the distillate in a watertrap. \After 1.5 hours, about 0.76 ml. of water was collected.Evaporation of the benzene solution to dryness under reduced pressure,and trituration of the residue with petroleum ether, gave about 11 g. ofan almost colorless solid that was dried under reduced pressure overcalcium chloride at 78 C.

Analysis.-Calcd. for C H NO: C, 80.41; H, 10.86; N, 4.08. Found: C,80.41; H, 10.92; N, 3.93.

A suspension of 1.82 g. (5 mmoles) of the above A enamine in 30 ml. ofethyl acetate was stirred vigorously while 2.0 ml. of 2.80 M (5.6mmoles) of cyanogen azide in ethyl acetate was added dropwise over aperiod of about 5 minutes. During this time the temperature of thereaction mixture was maintained at 2427 C. by external cooling with awater bath. During the addition of cyanogen azide, nitrogen was evolvedrapidly and in close to quantitative yield as judged by use of awet-test meter. After completion of the addition of cyanogen azide, thereaction mixture was stirred for 1.25 hours at room temperature and thenfiltered to remove the insoluble precipitate. After being rinsed withether and air-dried, the solid weighed 1.5 g., and melted at 245-250 C.with decomposition. Purification of a portion of the2a-(pyrrolidinocyanoiminomethyl) A nor 5a androstan 17fi-o1 wasaccomplished by dissolving 0.4 g. in 75 ml. of boiling benzene andfiltering the hot solution. To the filtrate 15 ml. of hexane was added.After 1 hour a white crystalline product weighing 0.3 g. was collectedby filtration. An analytical sample was prepared by a secondcrystallization from benzene-hexane and melted at 261.5- 263.5 C. withdecomposition.

max.

Nuiol nmx.

Proton magnetic resonance (CDCI internal tetramethylsilane): singlet at2.601- (OH; triplet at 6.421 (2,5- methylene hydrogens of pyrrolidine);singlet at 9.271 (angular CH with ratio of triplet to singlet about 4:6.

Analysis.-Calcd. for C H N O: C, 75.15; H, 9.72; N, 10.92. Found: C,74.82; H, 9.41; N, 10.94.

Chromatography of the crude product on neutral (activity grade III)alumina could also be used to purify the amidine. In this manner, 0.5 g.of crude product gave about 0.35 g. of white needles, MJP. 274275 C.dec. having an infrared spectrum identical to that obtained for theamidine purified by crystallization.

Analysis-Calcd. for C H N O: C, 75.15; H, 9.72; N, 10.96. Found: C,75.31; H, 9.60; N, 10.72.

In similar manner the acetate, propionate, valerate, undecanoate,bicyclo[2.2.2]-octane-1-carboxylate, adamantane-1-carboxylate, andhomoadamantane-l'-carboxylate esters of 17/3-hydroxy-5u-androstan-S-oneare converted to enamines and thence by the action of cyanogen azide tothe corresponding esters of 2a-(pyrrolidinocyanoiminomethyl)-A-nor-5u-androstan-175-01.

Instead of pyrrolidine, other equivalent cyclic secondary amines, suchas 4-methylpyrrolidine, piperidine or morpholine can be used to preparethe corresponding A enamines by reaction with androstanolone, and theseproducts can be treated with cyanogen azide as described to give thecorresponding Zea-(OYtIlOflIIlidlHO)-AIl'5otandrostan-17fl-ols. Thus,the t-[(4-methylpyrrolidino) cyanoiminomethyl], the12a-(piperidinocyanoiminomethyl) and the2a-(morpholinocyanoiminomethyl)-derivatives may be prepared.

Example2.17ot-methyl-2w(pyrrolidinocyanoiminomethyl)-A-nor-5a-androstan-176-01A solution of 20.0 g. (66 mmoles) of 17u-methyl-17i3-hydroxy-5a-androstan-3-one and 20 m1. of distilled pyrrolidine in 100ml. of benzene was heated under a reflux condenser fitted with a watertrap for 3.5 hours. Evaporation of the dry benzene solution to drynessgave a white solid which was dried further, to remove traces ofpyrrolidine, by heating it at 70-75 C. at about 0.1 mm. pressure for 1hour. The resulting, dry A -enamine was added to 400 ml. of ethylacetate which had been purified by passage through neutral (activitygrade I) alumina and the mixture was maintained at 20-20 C. withvigorous stirring while 30 ml. of 2.24 molar (67 mmoles) of cyanogenazide in ethyl acetate was added dropwise over a period of 0.5 hour.After 12 hours at room temperature the reaction had evolved a total of1540 ml. (94% of theory) of nitrogen. The crude, sparingly solublecyanoamidine, which was collected by filtration and washed with two50-rnl. portions of fresh ethyl acetate, weighed 17.2 g., M.P. 250-252"C. dec. Purification was accomplished by extracting the crude materialwith boiling toluene (150 ml./g.), filtering, and diluting the cooledfiltrate with equal volume of petroleum ether (B.P. 30-60" C.). Thisgave a total of 12.9 g. of17a-methyl-2-(pyrrolidinocyanoiminomethyl)-A-nor-5a-androstan-1719-01 asan almost colorless powder, M.P. 262264 C. dec.

73,53 3750, 3050 (OH), 2200 (GEN), 1568 (C=N) cm.-

xfigg 251 m (e=16,400)

Analysis.Calcd. for C H N O: N, 10.57. Found: N, 10.46.

In similar manner, 17a-ethyl-175-hydroxy-5a-androstan-3-one is convertedto an enamine and then to a 171:-ethyl-2a-(pyrrolidinocyanoiminoethyl)-A-nor 50c androstan-l7fl-ol andl7a-vinyl-17fi-hydroxy-5fl-androstan- 3-one is converted to an enamineand then to l7a-vinyl- 20;( pyrrolidinocyanoiminomethyl) A nor 5aandrostan-17B-ol.

As with the product of Example 1, other cyclic secondary amines may beemployed, such as those mentioned in Example 1.

Example 3.l7u -ethynyl 20c(pyrrolidinocyanoiminomethyl)-A-nor-5u-androstan-175-01 NaCN lit

The starting material, 17u-ethynyl-l7fl hydroxy5otandrostan-3-oue, wasprepared as follows:

Fourteen grams (50 mmoles) of 5u-androstane-3,l7-dione was converted to'3spyrrolidino-2randrosten-17-one with 10 ml. of pyrrolidone by aprocedure exactly analogous to that described in Example 2 above.

A solution of et-hynyl magnesium bromide in tetrahydrofuran was preparedby adding 50 m1. of 3 M methyl magnesium bromide to 200 ml. of drytetrahydrofuran, removing ml. of solvent by distillation, adding 300 ml.more of dry tetrahydro'furan, and passing purified acetylene into theice-cooled solution for 1.5 hours.

To the Grignard reagent was added the crude, carefully dried3-pyrro1idino-2-androstan-17-one and the mixture was heated at refluxtemperature for 5.5 hours. The recati-on mixture was distilled until25-0 ml. of solvent had been removed and, after cooling, it was pouredwith stirring into 1 liter of water containing g. of ammonium chloride.After 15 minutes, the white solid was collected by filtration andair-dried for 48 hours. Crystallization of 1 g. of the 15 g. of crudeproduct from dioxane-water, followed by washing with a small amount ofacetone, gave 0.5 g. of 17a-ethynyl-l7 6-hydroxy-5a-androstan-3-one,M.P. 293-295 C.

3330 CH), 1700 (0 0) emf The crude17x-ethynyl-17/3-hydroxy-5a-androstan-3- one was converted to the A-enamine with 15 ml. of pyrrolidine and 400 ml. of benzene by theprocedure described in Example 2. The dry enamine was treated with 22.0ml. of 2.24 M cyanogen azide in 500 ml. of ethyl acetate at 20-25 0.,giving a cyanoamidine which was soluble in the reaction medium.Filtration of the reaction mixture to remove a trace of brown gumfollowed by evaporation in vacuo to about 100 m1. and dilution withabout 400 ml. of petroleum ether gave 18 g. of creamcolored solid, M.P.-205 C., 17 g. of which was applied to a column of 500 g. of neutral(activity III) alumina in chloroform. Elution with benzene-petroleumether (3:1) then benzene-chloroform (4:1) gave in the latter eluate acolorless glass which, on trituration with benzene, gave 8.4 g. of17u-ethynyl-2a-(pyrrolidinocyanoiminomethyl)A-nor-Sa-androstan-1718-01,M.P. 252- 257" C. Analytical sample was prepared by crystalliaztion frombenzene, M.P. 254-255 C.; a 8 (0., 1.8 chloroform) 033,9 3020 (OH), 3330.011 2180 (G N), 1500 (C=N) cm.

Analysis.Calcd. for C25H37N3OZ C, 76.61; H, 9.15; N, 10.31. Found: C,76.64; H, 9.17; N, 10.20.

As in Example 1, other secondary amines, such as those mentioned in thatexample, may be used.

Example 4.2-formyl-A-nor-5a-androstan-1713-01 L i, CHBNHZ H20 17 NCN=CCi To a solution of 0.50 g. (1.3 mmoles) of2a-(pyrrolidinocyanoiminomethyl) A nor a androstan- 17/3-01 in about 100ml. of methylamine cooled in a Dry Ice-acetone bath was added enoughlithium ribbon to impart to the reaction mixture a persistent, dark bluecolor. After 1.5 hours, the blue solution was treated with sufficientammonium chloride to discharge its color. The methylamine was allowed toevaporate overnight and the residue was treated with water and sodiumhydroxide (the steroid at this point is an amine, soluble in aqueousacid) The aqueous mixture was extracted with ether and the extract waswashed with saturated sodium chloride solution, dried and evaporated.Application of a benzene solution of the residue to 15 g. of acidalumina (activity III) gave, on elution with 1:1 petroleum ether-benzeneand then with benzene, 174 mg. of 2g-formyl-A-nor-5aandrostan-17B-ol,M.P. 109-120 C. after crystallization from hexane, a 5 (c., 1.0chloroform).

03 19 3000, 3440 (OH); 2720, 1715 (CHO) 010:

Analysis.--Calcd. for C H O C, 78.57; H, 10.41. Found: C. 78.87; H,10.48.

The proton NMR spectrum shows that this aldehyde is a mixture of C-2epimers.

Example 5.-2-formyl-A-nor-5a-androstan-1748-01 The following processrepresents an improvement over that of Example 4:

To a stirred solution of 20.8 g. (54 mmoles) of 211-pyrrolidinocyanoiminomethyl) A nor 5a androstan- 1718-01 in about 700ml. of methylamine cooled in a Dry-Ice-acetone bath was added 9 g. (115mmoles) of ammonium acetate. After about minutes, 2.0 g. (excess) oflithium ribbon, which had been cut into small pieces and washed withcyclohexane, was added all at once. Exactly 5 minutes after persistentdark blue color first pervaded the reaction mixture, the mixture wastreated with sufficient ammonium chloride (about 30 g.) to discharge theblue color. The methylamine was allowed to evaporate overnight and theresidue was taken up in water and ether. The water layer was extractedwith ether and the ether layers were combined, washed with saturatedsodium chloride solution, and dried over sodium sulfate. Evaporation invacuo gave 17.2 g. of steroid as a white solid. Application of thisproduct as a solution in 70 ml. of benzene to a column of 500 -g. ofbasic alumina (activity HI) and elution with benzene gave 13.6 g. (86%yield of -2-formyl-A-nor-5a-androstan-17 3-o1 as a nearly colorlessglass.

,CHCl;

max.

3600, 3450 (OH); 2720 (CHO); (1715) (CHO) Example6.17a-methyl-2g-formyl-A-nor-5a-androstan- ---orn V This compound wasprepared from 12.0 g. of 17amethyl "2oz (pyrrolidinocyanoiminomethyl)A-nor-Saandrostan-17B-ol by a procedure analogous to that described inExample 4. The 17a-methyl-2-formyl-A-nor- 5a-androstan-17fl-ol wasobtained pure in 23% yield; M.P. 120.5-127.5 C.; a 21 (c., 1.2 CHCl E33700, 3500 (OH); 2780 (CHO); 1730 00) 0111- Analysis.-Calcd. for C H OC, 78.89; H, 10.59. Found: C, 79.13; H, 10.56.

The proton nuclear magnetic resonance spectrum (CCl tetramethylsilaneinternal) indicated that the aldehyde was a mixture of about 2 parts ofthe alpha formyland 1 part of the beta formyl-A-nor-steroids. Thealdehydic hydrogens appeared as two doublets centered at about 0351-;the less shielded hydrogen (area 1) undergoing coupling J =1.2 cps.; themore shielded hydrogen (area 2) undergoing coupling with J=2.0 cps.

Example 7 .-17a-methyl-2g-formyl-A-nor-5 a-androstan- The followingprocess represents an improvement over that of Example 6:

By a procedure analogous to that described in Example 5, 8.0 g. of17a-methyl-2a-(pyrrolidinocyanoiminomethyl)-nor-5a-androstan-1713-01 in400 ml. of methylarnine, with 3.5 g. of ammonium acetate and 0.85 g. oflithium, was converted to 5.7 g. of 2g-formyl-A-nor-5aandrostan-17B-ol,which after crystallization from acetonehexane gave 4.86 g. (80% yield)of crystalline product.

Likewise, 17o: ethyl 20c(pyrrolidinocyanoiminomethyl)-A-nor-5a-androstan-175-01 is reduced toethyl 25 formyl A nor 5a androstan 1713 01, and 17a vinyl 2a(pyrrolidinocyanoiminomethyl)- A-nor-5m-androstan-17fl-ol is reduced to17ot-Vil1Y1-2E- formyl-A-nor-Sa-androstan-17 3-01.

Example 8 .--2-formyl-A-nor-5 a-androstl-en- 1719-01 A solution of 1.16g. (4 mmoles) of 2g-formyl-A-nor- 5a-androstan-17fl-ol, 1.30 g. (5.8mmoles) of 2,3-dichloro- 5,6-dicyano-p-benzoquinone, and 60 mg. (0.3mmole) of p-toluenesulfonic acid monohydrate in 150 ml. of benzene washeated at reflux temperature for 1.3 hours. The mixture was cooled, 150ml. of ether was added, and the mixture was extracted with four 100-ml.portions of cold 5% sodium hydroxide. The organic layer was washed withwater and with saturated aqueous sodium chloride, and then dried oversodium sulfate and evaporated in vacuo, giving 1.15 g. of yellow solidwhich was chromatographed on 50 g. of neutral (activity III) alumina.Elution with benzene gave 1.0 g. of2-formyl-A-nor-5u-androstl-en-17/3-ol which, after crystallization fromacetonehexane, weighed 0.692 g. (60% yield); M.P. 137.5- 138.5 C.; a +77(c., 0.8 CHCl 11 9 59 3570, 3480 (OH), 1670 :0 1588 0:0 cm.-

A533 240 my (e=l4,100)

0 all A solution of 600 mg. (1.97 mmoles) of 17a-methyl-2-formyl-A-nor-5a-androstan-17fi-ol, 600 mg. of2,3-dichloro-5,6-dicyano-p-benzoquinone (2.6 mmoles), and 10 mg. ofp-toluenesulfonic acid monohydrate in 20 ml. of dioxane was heated atreflux temperature for 2.5 hours. Benzene was added to the reactionmixture and white, crystalline quinol, weighing 470 mg., was removed byfiltration. The filtrate was evaporated to dryness and then applied as asolution in benzene to 50 g. of neutral (activity III) alumina, Elutionwith benzene-petroleum ether (3:1) gave 120 mg. (20% yield) ofl7a-methyl-2-formyl- A-nor-5a-androst-1-en-17B-ol; M.P. 146.0-149.0 C.(acetone-hexane); u +5 0 (c., 0.8 CHCl 3159 3570, 3480 1667 (0:0 15800:0 cmf Example 10.2-formyl-A-nor-5 u-androst-1-en17fi-ol bicyclo-[2.2.2] -octane-1'-carboxylate O Hit-m Ethylbicyclo[2.2.2.]-octane-1-carboxylate (25 g.) [C. A. Grob, M. Ohta, E.Renk, A. Weiss, Helv. Chim, Acta, 41, 1191 (1958)] was saponified with10 g. of potassium hydroxide in ml. of methanol at reflux temperaturefor 24 hours. Acidification of an aqueous solution of the salt andextraction with ether gave the free acid. The acid was treated with 35ml. of thionyl chloride containing one drop of dimethylformamide firstat room temperature and then at reflux temperature for 1 hour, Excessthionyl chloride was removed under water pump vacuum and the residue wasdistilled through a spinning band column, giving 23.6 g. ofbicyclo[2.2.2]-0ctane-1-carboxylic acid chloride, B.P. 78 C./3.5 mm.

A solution of 520 mg. (3 mmoles) of the acid chloride and 432 mg. (1.5mmoles) of 2-formyl-A-nor-Sa-androst- 1-en-17/3-ol in 5 ml. of drypyridine was allowed to stand in a stoppered flask for 7 days and thenpoured into 100 ml. of water. Extraction with ether, followed by washingwith 5% aqueous hydrochloric acid and then 5% aqueous sodiumbicarbonate, drying, and evaporating in vacuo, gave 526 mg. of crudeester which was applied in benzene to a column of 30 g. of neutral(activity III) alumina. Elution with benzene-petroleum ether (1:1) gave306 mg. of 2-formyl-A-nor-5a-androst-l-en-17,8-01bicyclo[2.2.2]-octane-1-carboxylate which, after crystallization fromacetone-hexane, was obtained as needles. M.P. l82183 C.

max.

240 mu (e=15,000)

Example 11.2-formyl-A-nor-Sa-androst-1-en-17{3-ol adamantane--carboxylate Adamantane-l-canboxylic acid (10 g.) [H. Stetter, H.Schwarz, A. Hirsohhorn, Ber. 92, 1629 (1959)] was converted with thionylchloride and a trace of dimethylformamide to the corresponding acidchloride (8.90 g.), B.P. 70C./0.5 mm.

2-formyl-A-nor-5a-androst-1-en-17fl-ol (576 mg., 2.0 mmoles), 300 mg.1.5 mmoles) of adamantane-l-carboxylic acid chloride, 0.33 ml. (4mmoles) of pyridine, and 25 ml. of benzene was heated at refluxtemperature for 18 hours. The reaction mixture was cooled, diluted withether, washed successively with 5% aqueous hydroohloric acid, water, 5%aqueous sodium bicarbonate, and saturated sodium chloride solution. Thesolvent was dried and evaporated, giving 767 mg. of solid which waschromatographed on 30 g. of neutral (activity III) alumina, to give 164mg. of Z-formyl-A-nor-5a-androst- 1-en-17fl-oladamantane-1'-carboxylate, M.P. 205211 C. (from acetone-hexane).

EtOH max.

240 mp (e=15,000)

AnalysisCalcd. for G l-1 0 C, 79.95; H, 9.39. Found: C, 80.06; H, 9.24.

The same procedure, applied to homoadamantane-lcarboxylic acid (seeabove-cited reference) affords 2- 1 1formyl-A-nor-a-androst-1-en-17fi-ol homoadamantane-1'- carboxylate.

Likewise, using the acid chlorides of acetic acid, propionic acid,valeric acid, or dodecanoic acid, 2-formyl-A-nor-Sa-androst-1-en-17fi-ol is converted to the corresponding17fi-acetate, propionate, valerate or dodecanoate.

Example 12.2-formyl-A-nor-5a-androst-1-en-17-one v 1745 o-17 C=O 1676(CHO), 1600 o=o max.

AnalysisCalcd. for C H O C, 79.68; H, 9.15. Found: C, 79.59; H, 9.11.

A similar procedure applied to 2g-formyl-A-nor-5aandrostan-17-one.

Example 13.Ethylene acetal of 2-formy1-A-nor-5aandrost-1-en-17 B-o1 y2700, 3560 (on) em? (no band in carbonyl region) max.

The propylene acetal is obtained in the same manner, using 1,2-propyleneglycol.

Example 14.-'Ethylene acetal of 2-formyl-A-nor-5uandrost-1-en-17-oneEight grams of the acetal of Example 13 dissolved in 25 ml. of pyridine,was added to the product obtained by adding 7.0 g. of chromium trioxideto 135 ml. of pyridine at 15-25 C., and the whole was stirred at roomtemperature for 48 hours. The mixture was filtered through sinteredglass and the filter cake washed with three 100-ml. portions of 20%aqueous sodium dihydrogen phosphate, which was then added to thepyridine filtrate together with 700 ml. more of the 20% aqueous sodiumdihydrogen phosphate. Extraction of the filter cake with ether andextraction of the pyridine-water mixture with ether gave, on combinationof the dried ether extracts and evaporation in vacuo, 6.4 g. of theethylene acetal of 2-formyl-A- nor-5 oc-androst-l -enl7-one.

V 1740 Ont- (3-1? 0:0

max.

Example 15.2-formy1-A-nor-5a-androst-1-en-17-one A solution of 1.0 g. ofthe acetal of Example 14, 0.50 g. of p-toluenesulfonic acid, and 3 dropsof water in 10 ml. of ethanol was allowed to stand at room temperaturefor 2 hours and then diluted with water and extracted with ether. Theether solution was washed with 5% aqueous sodium bicarbonate, dried, andevaporated, giving 0.778 g. of 2-formyl-A-nor-5a-androst-1-en-17-one,identical to the product which is obtained in Example 12.

Example 16.--'Ethylene acetal of l7a-ethynyl-2-formyl-A-nor-Sa-androst-1-en-17B-ol A solution of 6.4 g. of the ethylene acetalof 2-formyl- A-nor-h-androst-l-en-l7-one in 200 ml. of drydimethylsulfoxide was treated with about 5 g. of sodium acetylide andthe mixture was allowed to stand at room temperature for 3 days. Thedark reaction mixture was poured into 1 liter of ice water and theaqueous mixture was extracted with ether, giving 6.67 g. of the ethyleneacetal of 17oc-ethynyl-2-formyl-A-nor-5a-androst-1-en-17fi-ol.

EH01: 3330 cm." (C 5 CH) Example17.17a-ethynyl-2-formyl-A-nor-5aandrostl-en- 1713-01 A solution of 6.6g. of the acetal of Example 16, with 1.0 g. of p-toluenesulfonic acidand 10 ml. of water in 30 m1. of ethanol, was allowed to stand at roomtemperature for 7 hours, and then poured into water. The aqueous mixturewas extracted with ether and the ether washed with 5% aqueous sodiumbicarbonate and dried. Evaporation of the solvent in vacuo gave a glasswhich was chromatographed on 200 g. of neutral (activity III) alumina togive about 4.6 g. of 17a-ethynyl-2-formyl-A-nor-Sa-androst-1-en-17fi-ol.

45155 1 75, 585 ornf Tests on experimental animals show that theZ-formyl- A-nor-steroids described in this specification are generallyof the androgenic type. Their useful properties include the ability toinhibit the production of pituitary gonadotrophin, a favorable ratio ofanabolic to androgenic activity, and antifertility activity.

For example, when 50 mg. per day of 17a-methyl-2-formyl-A-nor-Sa-androstan--01 was injected into the castrate member ofan intact female-castrate female parabiotic pair of rats, it caused amarked diminution of ovarian weight in the intact rat compared to theovarian weight in an untreated parabiotic pair. Thus, the test compoundinhibits castration-induced hypersecretion of pituitary gonadotrophin.

In the well known Hershberg test for anabolic and androgenic activity,Z-formyl-A-nor-5a-androstan-17 3-01,2-formyl-A-nor-5a-androst-1-en-17/3-ol, and the bicyclo[2.2.2]-octane-1'-carboxylate ofZ-fOIl'IlYl-A-IlOf-Saandrost-1-en-17fl-ol show a more favorable ratio ofanabolic to androgenic activity than testosterone.

Antifertility activity is exhibited by2-formyl-A-nor-5aandrostan-17fl-ol. Female rats receiving 5.0 mg./day ofthis compound beginning after ovulation and after mating had no uterineimplantation sites.

17a-methyl-2-formyl A nor-Su-androst-l-en-l7fl-ol shows, in young malerats, androgenic, anabolic and antigonadotrophic activity.

The 2a-(cyanoamidino)-A-nor-5a-androstanes of the invention are usefulin preparing the Z-formyl-A-norsteroids.

The acetals of the 2-formyl steroids are useful as precursors to C-17modified 2-formyl steroids; e.g., oxidation, reduction, or additionreactions can be carried out on the C-17 position while leaving intactthe protected formyl group at C-2. Examples 13-17 demonstrate thisuseful reaction sequence.

As many widely different embodiments of this invention may be madewithout departing from the spirit and scope thereof, it is to beunderstood that this invention is not limited to the specificembodiments thereof except as defined in the appended claims.

The embodiments of the invention in which an ex elusive property orprivilege is claimed are defined as follows:

1. A compound selected from the class consisting of (l)2-formyl-A-nor-5a-androstane derivatives of the formula Hist wherein Xis or the group is hydrogen or a hydrocarbon acyl group of 1 to 12carbons; R is H, CH C H CH=CH or CECH; and a is a single bond or adouble bond; (2) the acetals of the steroids of part (1) with ethyleneor 1,2-propylene glycol; and (3) 2m- (cyanoamidino)-A-nor-5a-androstanederivatives of the formula wherein R and R are as above 'and Q isalkylene of 4-5 chain carbon atoms and a total of 4-6 carbon atoms, oris 3-oxa-1,5-pentylene.

2. A compound of claim 1 of the formula 9. A process for preparing2a-(cyanoamidino)-A-nor- Sm-andrOstane derivatives of the formula NCNHal-- wherein R is hydrogen or a hydrocarbon acyl group of 1 to 12carbons; R is H, CH C H CH=CH or CECH, and Q is alkylene of 4-5 chaincarbon atoms and a total of 4-6 carbon atoms, or is 3-oXa-1,5-pentylenewhich comprises reacting at a temperature between about 0 and 50 C. in adry inert solvent, cyanogen azide with a steroid of the formula whereinR R and v are defined as above.

10. A process for preparing compounds of the formula wherein R ishydrogen or a hydrocarbon acyl group of 1 to 12 carbon atoms, and R isH, CH --C H or CH=CH which comprises reacting a compound of the formulaNCN wherein R and R are as defined above and Q is alkylene of 4-5 chaincarbon atoms and a total of 4-6 carbon atoms, or 3-oxa-1,5-pentylene,with an alkali metal at a temperature of between about and +20 C. in ananhydrous liquid medium selected from a l-2 carbon monoalkylamine orammonia, and hydrolyzing the reaction product under neutral to basicconditions.

References Cited Marsh et al., J. Am. Chem. Soc. vol. 86 pp. 4506-7(1964).

NICHOLAS S. RIZZO, Primary Examiner.

JOSE TOVAR, Assistant Examiner.

U.S. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,424,751 January 28, 196.

Richard M. Scribner It is certified that error appears in the aboveidentified patent and that said Letters Patent are hereby corrected asshown below:

Column 1, lines 20 to 25, that portion of the formula reading:

should read I l I l H H Column 13, line 28, before "is hydrogen" insertR Column 14, line 30, "v should read q Signed and sealed this 14th dayof April 1970.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, JR Attesting OfficerCommissioner of Patents

